This application addresses Challenge Area (01) Behavior, Behavioral Change, and Prevention and specific Challenge Topic, 01-DA-104: Functional Roles of Glia-Derived Factors in Mediating Drug Abuse. In line with NIDA's mission to support research that will improve drug abuse treatment, the long-term objective of the proposed translational research project is to develop treatments that effectively promote, hasten, or augment brain healing and cognitive recovery following methamphetamine (MA) dependence and abuse. Based on current support in the literature and our own findings, it is postulated that MA alters blood brain barrier permeability thereby exposing central nervous system (CNS) antigens and facilitating the development of anti-CNS responses. Thus, the central hypothesis to be tested with this project is that immunomodulatory agents can promote brain healing following MA use by reducing the accumulation of neuroinflammatory cells and glial-derived factors, and by reducing immunoreactivity to neuroantigens. The short-term objective to be addressed by this proposal is to test the proof of concept that immunotherapy using recombinant T-cell receptor ligands (RTLs) can regulate glia-derived and related immune factors, concurrently triggering healing responses in the brain and improving MA-induced cognitive impairment. Specific Aims to be addressed include: 1) to test the therapeutic efficacy of RTLs in improving cognitive function, decreasing neuronal degeneration, decreasing neuroinflammation, and preserving peripheral immune cell function in mice following chronic MA administration, 2) to test the in vitro therapeutic activity of RTLs in preserving peripheral immune cell function and reducing immunoreactivity to neuroantigen in mononuclear cells from MA dependent adults. Methods (Rodent Component): Following chronic MA versus saline administration, mice will be treated with RTL versus vehicle. Mice will undergo cognitive behavioral testing and blood and brain sample collection following the drug and intervention treatment phases. Immunohistochemistry, flow cytometric analysis, and multiplex assays will be used to measure blood and brain markers of neuronal degeneration and myelin repair, neuroinflammation, and peripheral immune function. Methods (Human Component): Blood samples will be collected from MA dependent adults, adults in early remission from MA dependence, and non-dependent controls. Mononuclear cells will be isolated for in vitro treatment with RTLs versus vehicle, followed by stimulation with recall antigens and neuroantigens. Multiplex assays will be used to evaluate the effects of RTL treatment and antigen exposure on inflammatory and anti- inflammatory mediators. Following the completion of our two year project, the scientific impact to the field of substance abuse research will be substantial and will potentially offer a new treatment strategy for MA dependence and abuse that could be readily tested in humans. Methamphetamine (MA) addiction is a growing epidemic in our nation, yet there are no FDA-approved medications to treat MA dependence. PUBLIC HEALTH RELEVANCE: Chronic MA abuse is known to cause neuronal injury and neuroanatomical changes that are associated with cognitive impairments, and the cognitive impairments that persist during recovery likely contribute to high relapse rates and poor treatment outcomes. Therefore, discovery of an immunotherapy that could improve brain repair and cognitive recovery following MA addiction would represent a major scientific breakthrough that could broadly impact addiction treatment and outcomes.